This is an application for a Mentored Patient-Oriented Career Development Award (K23) entitled Assessment of Cholinergic and Cognitive Function Using Pharmacologic ASL-perfusion MRI. Project Summary: This research project will investigate the value of combined pharmacologic manipulation and arterial spin-labeled perfusion MRI (pharmacologic ASL-pMRI) as an in vivo probe of cholinergic function. Methods to investigate cholinergic function in vivo are needed to better understand the role of acetylcholine in the physiology of the cerebral cortex, and in cognitive processes in health and in disease states. In this study, pharmacologic ASL-pMRI will be used to characterize the normal cerebral perfusion response to cholinergic manipulation in young healthy subjects. Cognitive measures will also be obtained and correlated with cerebral perfusion changes. Pharmacologic ASL-pMRI and cognitive testing will then be used to study how the cholinergic response is altered with normal aging and in delirium. The candidate's research interest is the application of pharmacologic neuroimaging to the study of cholinergic function in aging and age-related disease. The candidate's prior training includes basic science research in neuropharmacology, clinical training in behavioral neurology, and initial experience in functional imaging and clinical research under a NINDS-sponsored National Research Service Award. This proposed study will provide the candidate with more advanced training in the methods, applications, experimental design and analysis of functional MRI research, and will foster the candidate's development into an independent investigator with unique expertise in pharmacologic MRI. Didactic coursework in study design, statistics, ethics, and functional imaging will complement the research project. The research environment includes outstanding facilities for MRI and clinical research, and mentoring from a multi-disciplinary advisory committee. Relevance: The strengths of this application include the innovative use of pharmacologic ASL-pMRI in the research project, the expertise of the advisory committee, and the career development potential of the candidate. The proposed research project will elucidate the role of the cholinergic system in the common age-related neuropathologic conditions of dementia and delirium. This will in turn lead to new and more effective treatment strategies for these conditions, and help to improve health care and quality of life for the growing ranks of older Americans.